The present invention relates to an ingestible device capable of eliminating via removal or conversion, either constructive or destructive conversion, undesirable substances from the body.
For various reasons, including diet, substance use, illness, injury or surgery, patients may require supplementation of their natural body functions in order to remove waste or other products from their blood or gastrointestinal (GI) fluids. Several procedures known for this purpose are dialysis, hemodialysis, hemofiltration and hemodiafiltration. For example, dialysis is used to remove soluble waste and solvent from blood; hemofiltration is used to remove plasma water from blood; and hemodiafiltration is used to remove both unwanted solute (soluble waste) and plasma water from blood.
It is also known that a number of metabolic toxins such as mercaptans, free fatty acids, and conjugated bilirubin and endotoxins are completely bound with proteins in the bloodstream. Because of the size of the molecules and the strong interaction of the components of the protein-toxin complex, it is difficult or impossible to select and remove from blood toxins bound to, for example, albumin by traditional blood purification methods such as hemodialysis. Hemoperfusion is a blood purification method that works in conjunction with activated carbon or iron exchange resins that absorb materials including the protein-bound toxins.
It is well known that individuals that are diagnosed with chronic renal insufficiency can be treated with the aid of dialysis. Substances that are usually eliminated in the urine are removed with the assistance of a filtering device that contains a semi-permeable membrane. However, although dialysis supports life despite complete cessation of renal function, it fails to restore the patient to full functional normality and longevity. Patients affected by chronic uremia, undergoing periodic hemodialysis, frequently develop a clinical picture (also known in the literature as “post-dialytic syndrome”) characterized by marked muscular asthenia and a sensation of stupor, particularly evident immediately following dialysis. These conditions, attributed to the loss of carnitine during dialysis, may often last for several hours making difficult, if not impossible, to resume normal activity until these conditions subside.
In addition, during the course of the long term, hemodialysis complications can occur that include chronic accumulation of inorganic phosphate in dialysis patients. Phosphate agents can be administered orally and used as therapeutic agents, which are intended to prevent the reabsorption of food phosphates in the gastrointestinal tract.
Another treatment procedure that has been used is peritoneal dialysis, wherein a sterile saline solution is injected into the peritoneal cavity and remains there for a period of time. The saline solution is separated from the bloodstream by the peritoneum, which is a membrane that is semi-permeable selectively allowing only waste products to diffuse into the saline solution which is then drained out. In addition, osmosis of water through the peritoneum into the saline solution allows the removal of water, excess to overall body needs. This procedure, however, is semi-invasive and carries the risk of infection. Also, such a procedure is not suitable for the removal of a variety of substances, and may not be suitable for all patients.
A disadvantage of various of the above-mentioned treatments is that the biological fluids of the patient have to be transferred from the body, circulated through an exterior treating device, and then returning the biological fluids back to the patient. These treatments are typically done in a medical setting such as a hospital, and require the patient to travel to and from the hospital where the procedure is performed. This process can be time-consuming and disruptive to the normal activity of the daily life of the patient.
Also known are devices which deliver a drug agent to an environment of use. These devices are made with a wall formed of a material that is permeable to an external fluid and substantially impermeable to the beneficial agent. The wall is known to surround a compartment that contains the agent and a passageway through the wall for dispensing the agent.
The intestines (small and large) are recipient of normal local secretions (from the intestine wall) and secretions from exocrine glands of the stomach cells, pancreas and liver (through the bile). That includes hormones, electrolytes and glycoproteins (mucus). On the other hand, efflux and exsorption are processes where the intestine wall secretes into the intestine lumen substances in a way inverted to the intestinal absorption mechanisms (e.g., passive diffusion, facilitated diffusion and specific transport systems), including large molecules and drugs. During exsorption, energy-dependent membrane transporters pump drugs against their concentration gradient out of the cell and back into the intestinal lumen; compared with kidney and liver, little is known about the mechanisms underlying transport into the intestinal lumen.
Intestinal secretion of organic cations was first demonstrated in isolated guinea pig intestinal mucosa. Later studies demonstrated the active secretion of various organic cations into the intestinal lumen. P-glycoprotein, one of membrane transporter pump systems, localized in the intestinal brush-border membrane is involved in the active intestinal secretion of organic cations. In the case of a passive transport mechanism, the exsorption of drugs depends on the concentration gradients between the serosal and mucosal sides. The extent of secretion (exsorption) is determined by numerous factors such as the extent of binding to serum proteins, distribution volume, lipophilicity, pKa and molecular size of drugs, and the blood flow rate in the gut. In addition, changes in pH from ileum to colon affects solubility/dissolution or changes permeability of ionized drugs. Thus, exsorption is more likely for drugs which are characterized by relatively long half lives and low protein binding. Such drugs display unbound blood concentrations higher than the concentration in (gut wall) enterocytes, producing diffusion of drug from blood to enterocytes, followed by diffusion from enterocytes to the intestine lumen. When the lumen concentration is lower than the enterocyte concentration, the “Ka” becomes negative, and exsorption will occur; clearly, if the Ka can reach negative values, it is not constant. This can happen for both oral and IV administered drugs. Re-absorption of the exsorpted drug could cause an increase of its levels at later time points.
Studies have uncovered that specific transport systems such as P-glycoprotein, organic cation and organic anion transporters are involved in active intestinal secretion of drugs such as Immunesuppressives (Cyclosporin, Tacrolimus), Steroids (Aldosterone, Hydrocortisone, dexamethasone), HIV protease inhibitors (Amprenavir, Indinavir, Nelfinavir, Ritonavir, Saquinavir), Cardiac drugs (Digoxin, Digitoxin, Quinidine, Verapamil), Anticancer drugs (Etoposide, Teniposide, Doxorubicin, Paclitaxel, Docetaxel, Vinblastine, Vincristine, Mitoxantrone) and numerous others (Erythromycin, Loperamide, Ondansetron, Fexofenadine).
Abnormal secretions from small and large bowel tumors, pancreas or hepatic system tumors are also produced and secreted into the intestine lumen producing local or systemic effects (following absorption).
Collection of secreted or exsorpted molecules from the gut lumen can lead to reduction or elimination of their local effect on the gut wall. For example, in the case of gastrointestinal hormones, reduction of their concentration or elimination thereof would inhibit cascades that lead to other events or eliminate digestion of certain molecules, thus leading to decrease of absorbable substances in the lumen. These actions would aid in the elimination of toxic levels of substances (endogenous or exogenous), may alter the course of medical conditions or diseases, and may also be used to control levels of drugs which participate in the intestinal exorption process or avoid the absorption of certain nutrients enabling weight control or treatments of various disorders.
In addition, a major function of the intestine is to form a defensive barrier to prevent absorption of harmful substances from the external environment. This protective function of the intestinal mucosa is effected through selective permeability. Evidence indicates that permeability of the intestinal mucosa is increased in most patients with Crohn's disease and in 10% to 20% of their clinically healthy relatives. Permeability is also increased in celiac disease, leaky gut syndrome and in trauma, burns, and as a result of nonsteroidal anti-inflammatory drug treatment.
The major determinant of the rate of intestinal permeability is the opening or closure of the tight junctions between enterocytes in the paracellular space. The tight junctions are narrow belts that circumferentially surround the upper part of the lateral surfaces of the adjacent epithelial cells to create fusion points or “kisses”. They are involved in maintaining the cellular polarity and in the establishment of compositionally distinct fluid compartments in the body. Tight junctions are formed by many specific proteins and are connected with the cytoskeleton. The intestinal tight junctions are highly dynamic areas and their permeability can change in response to both external and intracellular stimuli. In fact, the tight junctions play an important role in the regulation of the passive transepithelial movement of molecules. A number of signalling molecules have been implicated in the regulation of tight junction function, including Ca++, protein kinase C, G proteins and phospholipase A2 and C. In many intestinal and systemic diseases, changes in intestinal permeability are related to alteration of tight junctions as an expression of intestinal barrier damage. Moreover, permeability of the tight junctions can be modified by bacterial toxins, cytokines, hormones, drugs, trauma and burns.
Zonula occludens toxin derived from Vibrio cholerae interacts with a specific intestinal epithelial surface receptor, with subsequent activation of a complex intracellular cascade of events that regulate tight junction permeability.
Zonulin, a novel human protein which is similar to the Vibrio cholerae derived Zonula occludens toxin, induces tight junction disassembly and subsequent increase in intestinal permeability in intestinal epithelia. Zonulin likely plays a pivotal role in tight junction regulation during developmental, physiological, and pathological processes, including tissue morphogenesis, movement of fluid, macromolecules and leukocytes between the intestinal lumen and the interstitium, and inflammatory/autoimmune disorders. Zonulin expression is elevated in intestinal tissues during the acute phase of Celiac disease, a clinical condition in which tight junctions are opened and permeability is increased.
Enteric infections have been implicated in the pathogenesis of both food intolerance and autoimmune diseases secondary to the impairment of the intestinal barrier. Small intestines exposed to either pathogenic or nonpathogenic enteric bacteria secrete zonulin. Such secretion is independent of intestinal origin (species) or the virulence of the microorganisms tested; secretion occurrs only on the luminal side of the small-intestinal mucosa, and is followed by a decrease in small-intestinal tissue resistance (transepithelial electrical resistance) which is secondary to the zonulin-induced tight junction disassembly evident from the disengagement of the zonula occludens 1 protein from the tight junctional complex. This zonulin-driven opening of the paracellular pathway may represent a defensive mechanism, which flushes out microorganisms and contributes to the host response against bacterial colonization of the small intestine.
Modulation of intestinal permeability constitute an innovative method of oral drug delivery by enhancing paracellular permeability while modulating epithelial tight junctions. Zonula occludens toxin and human Zonulin are considered candidates for such use. Sodium salts of medium-chain fatty acids, sodium caprate (a dairy product constituent) in particular, have been used as absorption-enhancing agents to promote transmucosal drug absorption. Superporous hydrogel (SPH) and SPH composite (SPHC) also may be used as peptide drug permeation enhancers. Melittin is the major active ingredient in bee venom and has been widely studied for its membrane-fusion property and has been considered as a novel absorption enhancer. Chitosans, other absorption enhancing agents, interact with the cell membrane resulting in a structural reorganization of tight junction-associated proteins which is followed by enhanced transport through the paracellular pathway; the binding and absorption enhancing effects of chitosans on epithelial cells are mediated through their positive charges.
Taking advantage of the new knowledge applied in pharmacology for drug delivery by permeability modulation to increment absorption, exsorption of blood molecules can also be enhanced when using such agents in conjunction with an element that selectively could bind the undesired molecules for further excretion. Also removal of excessive zonulin produced inside the intestine lumen may alter the disease course in many conditions by restoring its defensive barrier function.
A known group of polymers called non-absorbed polymers are designed to operate in the gastrointestinal tract and selectively bind specific target molecules. These polymers are orally administered in capsule or tablet form, pass through the stomach and into the intestines where targeted molecules bind with the polymer, pass through the intestinal tract, and are excreted from the body.
These and other orally administered treatments suffer from many disadvantages. For example, several therapeutic agents which could have been useful in the context of converting gastrointestinal constituents into a non-toxic state, are in fact sensitive to the pH levels characterizing the gastrointestinal environment, and would be destroyed in the gastrointestinal tract, therefore such agents cannot effectively be used. In addition, many therapeutic agents cause damage to one or more organs or tissues of the gastrointestinal tract. The mechanisms for such damage may involve changes in the quality and quantity of mucous, bicarbonate secretion and mucosal blood flow of the gastrointestinal tract. Many agents are weak acids and in the acidic environment of the stomach do not ionize, thus making them more able to penetrate the gastric mucosal barrier and gain entrance into mucosal cells. Once inside mucosal cells, the neutral intracellular pH causes the compounds to ionize. The accumulation of the resulting ions in the cell is believed to interfere with other intracellular stabilizing mechanisms thereby enhancing the possibility of damage. When these agents are given systemically they can produce deep clinically significant ulcers. Once the intestinal mucosa is damaged, bacteria, toxins and allergens normally prevented from penetrating the gastrointestinal system can permeate into the bloodstream, where they are carried into all parts of the body, both triggering and exacerbating symptoms. Also bowel habits may be disturbed producing constipation. Thus, the gain from using such agents is smaller than the damage caused thereby.
There is thus a widely recognized need for, and it would be highly advantageous to have, an ingestible device which is capable of removing or converting undesirable gastrointestinal substances, or metabolites, which is devoid of the above limitations.